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Glucose transporter GLUT1 plays a primary role in the glucose metabolism of cancer cells. Here, we found that cardiac glycosides (CGs) such as ouabain, oleandrin, and digoxin, which are Na+,K+‐ATPase inhibitors, decreased the GLUT1 expression in the plasma membrane of human cancer cells (liver cancer HepG2, colon cancer HT‐29, gastric cancer MKN45, and oral cancer KB cells). The effective concentration of ouabain was lower than that for inhibiting the activity of Na+,K+‐ATPase α1‐isoform (α1NaK) in the plasma membrane. The CGs also inhibited [3H]2‐deoxy‐ d‐glucose uptake, lactate secretion, and proliferation of the cancer cells. In intracellular vesicles of human cancer cells, Na+,K+‐ATPase α3‐isoform (α3NaK) is abnormally expressed. Here, a low concentration of ouabain inhibited the activity of α3NaK. Knockdown of α3NaK significantly inhibited the ouabain‐decreased GLUT1 expression in HepG2 cells, while the α1NaK knockdown did not. Consistent with the results in human cancer cells, CGs had no effect on GLUT1 expression in rat liver cancer dRLh‐84 cells where α3NaK was not endogenously expressed. Interestingly, CGs decreased GLUT expression in the dRLh‐84 cells exogenously expressing α3NaK. In HepG2 cells, α3NaK was found to be colocalized with TPC1, a Ca2+‐releasing channel activated by nicotinic acid adenine dinucleotide phosphate (NAADP). The CGs‐decreased GLUT1 expression was significantly inhibited by a Ca2+ chelator, a Ca2+‐ATPase inhibitor, and a NAADP antagonist. The GLUT1 decrease was also attenuated by inhibitors of dynamin and phosphatidylinositol‐3 kinases (PI3Ks). In conclusion, the binding of CGs to intracellular α3NaK elicits the NAADP‐mediated Ca2+ mobilization followed by the dynamin‐dependent GLUT1 endocytosis in human cancer cells. [ABSTRACT FROM AUTHOR]

Abstract: Tumor growth of colorectal cancers accompanies upregulation of cyclooxygenase-2, which catalyzes a conversion step from arachidonic acid to prostaglandin H2 (PGH2). Here, we compared the expression levels of thromboxane synthase (TXS), which catalyzes the conversion of PGH2 to thromboxane A2 (TXA2), between human colorectal cancer tissue and its accompanying normal mucosa. It was found that TXS protein was consistently upregulated in the cancer tissues from different patients. TXS was also highly expressed in human colonic cancer cell lines. Depletion of TXS protein by the antisense oligonucleotide inhibited proliferation of the cancer cells. This inhibition was rescued by the direct addition of a stable analogue of TXA2. The present results suggest that overexpression of TXS and subsequent excess production of TXA2 in the cancer cells may be involved in the tumor growth of human colorectum. [Copyright &y& Elsevier]

Abstract: Na+,K+-ATPase is a housekeeping pump in virtually all animal cells. Recently, cardiac glycosides that inhibit Na+,K+-ATPase have been reported to be candidate for novel anticancer drug. Here, we investigated clinical significance of Na+,K+-ATPase α1-isoform (α1NaK), α2-isoform (α2NaK) and α3-isoform (α3NaK) in hepatocellular carcinoma (HCC). Interestingly, the expression levels of α3NaK protein in HCC tissues were significantly higher than those in the accompanying non-tumor tissues, whereas no significant increases in expression of α1NaK and α2NaK proteins were observed in HCC compared to non-tumor tissues. The ouabain (10μM)-sensitive K+-ATPase activities (Na+,K+-ATPase activities) in the membrane fraction from HCC tissue were significantly higher than those from non-tumor tissues. The Na+,K+-ATPase activity was positively and significantly correlated with the expression level of α3NaK. Apparent affinity for Na+ in the Na+,K+-ATPase activity in HCC tissues was significantly lower than that in non-tumor tissues, consistent with an elevated expression of α3NaK relative to α1NaK. Our results suggest that overexpression of α3NaK increases the Na+,K+-ATPase activity of HCC cells. [Copyright &y& Elsevier]